title: Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier.
abstract: Diabetic retinopathy regresses after spontaneous infarction or surgical ablation of pituitary gland. Growth hormone deficiency seems to be a protective factor for development of diabetic retinopathy in dwarfs. Despite the same glycemic control, development of diabetic retinopathy is significantly higher in pubertal subjects than pre-pubertal subjects. These evidences indicate a strong relationship between growth hormone and progression of diabetic retinopathy. Insulin like growth factor-1 (IGF-1) is the most important mediator of effects of growth hormone (GH). It stimulates IGF-1 receptor. Insulin analogues also stimulate IGF-1 receptor. Therefore insulin analogues may show similar effects like growth hormone and deteriorate diabetic retinopathy. However we suggest that impairment degree of inner blood-retinal barrier should be considered for this claim. We hypothesize that insulin analogues have dual effects (beneficial and worsening) depending on stage of impairment of inner blood-retinal barrier. Insulin analogues protect pericytes and blood-retinal barrier by decreasing blood glucose level. Analogues may pass into the retinal tissue in very low amounts when inner blood-retinal barrier is intact. Therefore, insulin analogues may not deteriorate diabetic retinopathy but also have beneficial effect by protecting blood-retinal barrier at this stage. However, they may pass into the retinal tissue in much more amounts when inner blood-retinal barrier impairs. Analogues may deteriorate cellular composition of retina through stimulation of IGF-1 receptors. A number of different cell types, including glia, retinal pigment epithelial cells and fibroblast-like cells have been identified in diabetic epiretinal tissues. Insulin analogues may cause proliferation in these cells. A type of glial cell named Non-astrocytic Inner Retinal Glia-like (NIRG) cell was identified to be stimulated and proliferate by IGF-1. IGF has been reported to generate traction force in retinal pigment epitelium (RPE) and mullerian cells. Mullerian cells also support inner blood-retinal barrier. Insulin analogues may cause proliferation in glial cells and generate traction force in RPE and mullerian cells by stimulating IGF-1 receptor. These effects of analogues may increase after deterioration of inner blood-retinal barrier and cause structural changes in retinal tissue. Deterioration of cellular structure may contribute to impairment of inner blood-retinal barrier, facilitate anjiogenesis and influence vitreoretinal interface. Therefore we suggest that insulin analogues should be used carefully after impairment of inner blood-retinal barrier. Analogues that bind with lesser affinity to IGF-1 receptor should be chosen after impairment. Pharmacologic agents may be developed to antagonize effect of insulin analogues on IGF-1 receptors.
authors.affiliation: Resident of Ophthalmology, GATA Haydarpasa Training Hospital, Department of Ophthalmology, Istanbul, Turkey. Electronic address: abdullahkayamd@gmail.com.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kaya
authors.forename: Taner
authors.initials: T
authors.lastname: Kar
authors.forename: Yakup
authors.initials: Y
authors.lastname: Aksoy
authors.forename: Veysel
authors.initials: V
authors.lastname: Özalper
authors.forename: Barbaros
authors.initials: B
authors.lastname: Başbuğ
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D001813:Blood-Retinal Barrier / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D013006:Growth Hormone / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D061385:Insulins / Q000009:adverse effects / Q000494:pharmacology*; D008954:Models, Biological; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D061385:Insulins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D017526:Receptor, IGF Type 1